ArticleThe American journal of pathology2011
Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain.
Article in The American journal of pathology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 98 citations in OpenAlex.
- Review
- Apoptotic cell death in disease-Current understanding of the NCCD 2023.Cell death and differentiation · 2023Review
- N,N-dimethylacetamide targets neuroinflammation in Alzheimer's disease in in-vitro and ex-vivo models.Scientific reports · 2023Article
- Discovery of novel CSF biomarkers to predict progression in dementia using machine learning.Scientific reports · 2023Article
- The role of ADAM17 in cerebrovascular and cognitive function in the APP/PS1 mouse model of Alzheimer's disease.Frontiers in molecular neuroscience · 2023Article
- The Implication of Glial Metabotropic Glutamate Receptors in Alzheimer's Disease.Current neuropharmacology · 2023Review
- Neuroinflammatory Signaling in the Pathogenesis of Alzheimer's Disease.Current neuropharmacology · 2022Review
- Synergistic influence of cytokine gene polymorphisms over the risk of dementia: A multifactor dimensionality reduction analysis.Frontiers in aging neuroscience · 2022Article
- Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer's Disease: Possible Therapeutic Role of KFrontiers in cellular neuroscience · 2022Review
- Microglia in Alzheimer's Disease: a Key Player in the Transition Between Homeostasis and Pathogenesis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Targeting innate immunity to protect and cure Alzheimer's disease: opportunities and pitfalls.Molecular psychiatry · 2021Review
- Molecular and cellular pathways contributing to brain aging.Behavioral and brain functions : BBF · 2021Review
- Modulating innate immune activation states impacts the efficacy of specific Aβ immunotherapy.Molecular neurodegeneration · 2021Article
- Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults.Brain, behavior, and immunity · 2021Article
- Strategies to Target ADAM17 in Disease: From its Discovery to the iRhom Revolution.Molecules (Basel, Switzerland) · 2021Review
- Mechanisms of the Procognitive Effects of Xanthotoxin and Umbelliferone on LPS-Induced Amnesia in Mice.International journal of molecular sciences · 2021Article
- Immunomodulation with IL-17 and TNF-α in spondyloarthritis: focus on the eye and the central nervous system.Therapeutic advances in musculoskeletal disease · 2021Review
- Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms.Frontiers in neuroscience · 2021Review
- Current Evidence on the Protective Effects of Recombinant Human Erythropoietin and Its Molecular Variants against Pathological Hallmarks of Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis.Neural regeneration research · 2020Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-α, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. We previously demonstrated that the expression of TNF-α is increased in AD mice at ages preceding the development of hallmark amyloid and tau pathological features and that long-term expression of this cytokine in these mice leads to marked neuronal death. Such observations suggest that TNF-α signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-α receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-α receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-α. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-β phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-β peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD.
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